This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your Institutional Review Board (IRB) from May 14, 2013, to May 29, 2013, by an investigator from the FDA’s Seattle District Office. This inspection was conducted to determine whether your IRB is in compliance with applicable federal regulations. IRBs that review investigations of devices must comply with applicable provisions of Title 21, Code of Federal Regulations (CFR) Part 56 - Institutional Review Boards, Part 50 - Protection of Human Subjects, and Part 812 - Investigational Device Exemptions (IDE). This letter also requests prompt corrective action to address the violations citedand discusses your IRB’s written responses dated June 20, 2013, June 27, 2013, and July 31, 2013, to the noted violations.

The inspection was conducted under a program designed to ensure that data and information contained in requests for IDEs, premarket approval applications, and premarket notification submissions are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Our review of the inspection report prepared by the district office revealed serious violations of 21 CFR Part 50 - Protection of Human Subjects and Part 56 - Institutional Review Boards, which concern requirements prescribed under section 520(g) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. § 360j(g). At the close of the inspection, the FDA investigator presented an inspectional observations Form FDA 483 and discussed the observations listed on the form with IRB Chairman Ronald B. Lahner. The deviations noted on the Form FDA 483, your IRB’s written responses, and our subsequent review of the inspection report, are discussed below.

1.Failure to ensure that research involving children is in compliance with 21 CFR Part 50, Subpart D, at the time of initial review of research [21 CFR 56.111(c)]

An IRB is required to review clinical investigations involving children as subjects under 21 CFR Part 50, Subpart D, Additional Safeguards for Children in Clinical Investigations, and approve only investigations that satisfy the criteria identified in 21 CFR 50.51, 50.52, or 50.53. Each of these sections requires the IRB to find that the investigation satisfies the criteria specified for the applicable risk category.

Based on a review of your IRB meeting minutes, your IRB approved the following clinical investigations without finding that the investigations satisfy the criteria in applicable section of Subpart D:

In your IRB’s written responses dated June 20, 2013, you acknowledge the IRB’s shortcomings regarding this violation. You state that you will require IRB member and coordinator retraining, as well as added oversight on studies with minors as subjects until such time as all policies are strictly followed and in full compliance with 21 CFR Part 50, Subpart D. You also state that the IRB’s policy and guideline document will be amended to require full IRB consideration of all studies involving minors. Moreover, you note that the IRB policies and guidelines set appropriate terms for, among other things, “risk analysis with appropriate review based on risk.” This response is inadequate because it lacks sufficient detail and supporting documentation to ensure that these actions will be implemented and will prevent future recurrence of this violation.

2.Failure to notify investigators of modifications required to secure IRB approval of the research activity [21 CFR 56.109(e)]

An IRB is required to notify investigators and the institution in writing of its decision to approve or disapprove proposed research, or of modifications required to secure IRB approval of the research.

Your IRB failed to notify investigators of the conditions of approval for the following clinical investigations:

Your IRB’s failure to notify clinical investigators of the conditions of approval for the clinical investigations listed above is a serious violation of your IRB’s responsibilities. A primary responsibility of an investigator is to conduct the clinical investigation according to the investigational plan and the IRB’s conditions of approval. This helps to ensure that data collected is consistent and accurate, and that appropriate human subject protections are being followed. Clinical investigators would not be able to fulfill this responsibility if they are not aware of the IRB’s conditions of approval. As a result of your IRB’s actions, research subjects, including children, may have been placed at increased risk of harm and their rights may not have been adequately protected.

In your IRB’s written responses, you note that the IRB policies and guidelines set appropriate terms for, among other things, principal investigator and sponsor notifications. This response is inadequate because your procedures do not require the IRB to notify investigators of the conditions of approval in writing, nor does your response include a plan to prevent recurrence of this violation.

3.Failure to review proposed research at convened meetings at which a majority of the members of the IRB are present [21 CFR 56.108(c)]

Except when an expedited review procedure is used, an IRB is required to review proposed research at convened meetings at which a majority of the IRB members are present, including at least one member whose primary concerns are in nonscientific areas.

Your IRB reviewed FDA-regulated research at meetings at which less than a majority of the members were present in the following instances:

On February 20, 2012, your IRB issued an approval letter for the investigation titled, “(b)(4),” but your IRB did not approve this investigation at a convened meeting. Your IRB previously voted to defer review on this investigation at the December 7, 2011, meeting.

On December 1, 2010, your IRB voted on and approved research with (b)(4) of (b)(4) members present.

On September 1, 2010, your IRB voted on and approved research with (b)(4) of (b)(4) members present.

In your IRB’s written responses, you note that the IRB policies and guidelines set appropriate terms for, among other things, meeting attendance. This response is inadequate because it does not include a plan to prevent recurrence of this violation.

An IRB is responsible for conducting continuing review of research covered by these regulations, including certain research involving Humanitarian Use Devices (HUD), at intervals appropriate to the degree of risk, but not less than once per year.

Your IRB failed to conduct continuing review of research involving the JOSTENT GraftMaster HUD at least once per year. Specifically, your IRB initially approved clinical use of the device on May 11, 2006, and did not conduct continuing review until August 1, 2007, and February 24, 2009.

Other than to concur with this violation, your IRB’s written responses do not address corrective and preventive actions for this violation.

An IRB is required to prepare and maintain adequate documentation of IRB activities including, but not limited to: copies of all research proposals reviewed; IRB meeting minutes; progress reports submitted by investigators; correspondence between the IRB and the investigators; and a list of IRB members.

Your IRB failed to prepare or maintain adequate documentation. Such instances include, but are not limited to, the following:

The IRB meeting minutes lack sufficient detail to show the votes of all attending members for the IRB meetings held on February 6, 2013, January 2, 2013, December 5, 2012, December 7, 2011, and August 3, 2011.

Your IRB failed to maintain a copy of the roster of IRB members for changes dated February 2013, November 2012, October 2011, and June 2011.

In your IRB’s written responses, you note that the IRB policies and guidelines set appropriate terms for, among other things, documentation, complete meeting minutes, and rosters. This response is inadequate because it does not include a plan to prevent recurrence of this violation.

6.Failure to prepare and maintain written procedures for IRB activities [21 CFR 56.115(a)(6)]

An IRB is required to prepare and maintain written procedures for IRB activities including, but not limited to: initial and continuing review of research; reporting its findings and actions to the investigator and the institution; determining which projects require review more often than annually; ensuring prompt reporting to the IRB of changes in research activity; and ensuring that changes in approved research may not be initiated without IRB review and approval.

Your IRB lacks written procedures for reporting its findings and actions to the investigator and the institution and for determining which projects require review more often than annually.

It is critical that your IRB prepare and maintain its written procedures for the review of research. Such procedures will help to ensure that research is reviewed in a timely manner and that the findings are adequately reported to the institution and the clinical investigator. Your IRB’s lack of written procedures for the review of research can compromise the rights, safety, and welfare of research subjects and decrease the integrity and validity of research data.

In your IRB’s written responses, you note that the IRB policies and guidelines set appropriate terms for, among other things, documentation. This response is inadequate because it fails to address written procedures for reporting IRB findings and actions to the investigator and the institution and for determining which projects require review more often than annually.

The violations discussed in this letter are not intended to be an all-inclusive list of problems that may exist at the IRB. The IRB is responsible for ensuring compliance with the Act and applicable regulations.

Within 15 working days of receiving this letter, please provide documentation of the additionalactions that you have taken or will take to correct these violations to prevent the recurrence of similar violations, and a plan to monitor the effectiveness of your corrective actions. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you.

Your response should reference “CTS # EC120539/E001” and be sent to:

Attention: Linda Godfrey

Food and Drug Administration

Center for Devices and Radiological Health

Office of Compliance

Division of Bioresearch Monitoring

10903 New Hampshire Avenue

Building 66, Room 3446

Silver Spring, Maryland 20993-0002.

A copy of this letter has been sent to FDA’s Seattle District Office, 22215 26th Ave SE, Suite 210, Bothell, WA 98021-4421. Please send a copy of your response to that office.

The Division of Bioresearch Monitoring has developed introductory training modules in FDA-regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA-regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/ucm162015.htm.

If you have any questions, please contact Linda Godfrey at (301) 796-5654 or via e-mail at Linda.Godfrey@fda.hhs.gov.